tbuckley/cabot-search huggingface dataset:
Abstract 4669: A patient derived xenograft model for lung adenocarcinoma using Obagel®, a human derived hydrogel
Authors: Cecilia Sanchez, Jonathan Nakashima, Kristein King, Trivia Frazier
Journal: Cancer Research (2023)

Abstract Patient Derived Xenografts (PDXs) are valuable disease models as they preserve the tumor microenvironment’s structure, providing the most clinically relevant in vivo testing platform. Nevertheless, most of those models still use animal derived hydrogels as scaffolds for patient derived cells, reducing the potential to fully mimic the physiological microenvironment of the disease and human condition. ObaGel® is a human-derived hydrogel successfully deployed for supporting 3D cell culture, organoid, perfusion bioreactor, and/microphysiological system development for studying obesity, type II diabetes, and various forms of related cancers. Here we are investigating the use of Obagel® in the in-vivo development of a PDX-derived culture of lung adenocarcinoma and compare its performance to currently used animal derived hydrogels. Methods: 3 × 10^6 CRT00295 Non-small cell lung adenocarcinoma cells in 100ul 50:50 indicated Gel in PBS per injection site; the study used 10 NOG mice per condition. Results: The results indicated that ObaGel® performed similarly in terms of engraftment and tumor kinetics compared to animal derived hydrogels such as Cultrex, Geltrex, and Matrigel, using a patient-derived xenograft culture of lung adenocarcinoma. Conclusions: Our data supports the use of a human-derived hydrogel for PDX models, ObaGel® performs equivalently to animal derived hydrogels to support tumor volume over time. The use of a human derived hydrogels as scaffolds for PDX models provide a better humanized local microenvironment for lung adenocarcinoma. Obagel® can also be adapted for use as xenografts in other tissue/disease models Citation Format: Cecilia Sanchez, Jonathan Nakashima, Kristein King, Trivia Frazier. A patient derived xenograft model for lung adenocarcinoma using Obagel®, a human derived hydrogel. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4669.
Abstract 451: AICAR targets oncogenic signaling pathways of MUC1-CT
Authors: Fareesa Aftab, Alice Rodriguez-Fuguet, Luis Silva, Ikei S. Kobayashi, Jiao Sun, Katerina Politi, Elena Levantini, Wei Zhang, Susumu S. Kobayashi, Wen Cai Zhang
Journal: Cancer Research (2023)

Abstract Lung cancer cells overexpress oncogenic mucin 1 (MUC1), whose C-terminal active subunit (MUC1-CT) is involved in lung tumor formation. Although a specific peptide against MUC1-CT has effectively blocked the MUC1 signaling pathway, intrinsic metabolites targeting MUC1 were not well studied. 5-aminoimidazole-4-carboxamide riboside (AICAR) is a purine biosynthesis intermediate and an analog of adenosine. Our study showed that high AICAR reduced lung tumor cell growth by increasing DNA damage and cell apoptosis. MUC1 was validated as one of the leading AICAR-binding proteins by virtual target screening and thermal stability assay. AICAR treatment dramatically degraded MUC1-CT at protein levels. Whole transcriptome analysis demonstrated that AICAR negatively regulated the Janus kinase (JAK) signaling pathway. Duolink proximity ligation assay revealed that JAK1 interacted with MUC1 directly, and AICAR treatment impaired this protein-protein interaction. Increased epidermal growth factor receptor (EGFR) activity was linked to upregulated expression of MUC1-CT in tissues from an EGFR transgenic mouse lung cancer model. AICAR treatment reduced phosphorylated EGFR, JAK1, and MUC1-CT in lung cancer cells. A mono-treatment with AICAR reduced tumor formation in a mouse lung xenograft model. Combination therapy with AICAR and small-molecule inhibitors against JAK1 or mutant EGFR reduced the growth of lung tissue-derived tumor organoids. Thus, our study has first disclosed a new ligand repressing the MUC1 activity in lung cancer that disrupts protein-protein interactions between MUC1-CT and other oncogenic proteins. Citation Format: Fareesa Aftab, Alice Rodriguez-Fuguet, Luis Silva, Ikei S. Kobayashi, Jiao Sun, Katerina Politi, Elena Levantini, Wei Zhang, Susumu S. Kobayashi, Wen Cai Zhang. AICAR targets oncogenic signaling pathways of MUC1-CT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 451.
Abstract 698: Developing a self-targeted cancer immunotherapy using engineered whole tumor cell-based vaccine
Authors: Kok-Siong Chen, Natalia Claire Mendonca, Paulo Borges, Khalid Shah
Journal: Cancer Research (2023)

Abstract The administration of inactivated tumor cell lysate is known to induce a potent antitumor immune response, however, their therapeutic efficacy as shown in Phase I-III clinical trials is limited. This could be attributed to the lack of direct cytotoxic effect on tumor cells and the inability to trigger a strong antitumor immune response. Unlike inactivated tumor cells, living tumor cells possess a unique potential to home to and self-target tumors. Therefore, repurposing the tumor cells’ self-homing property and natural source of neoantigens is advantageous for self-targeted cancer immunotherapy. In this study, we developed a genetically engineered living whole cancer cell-based therapeutic with direct tumor killing and immunostimulatory roles. We switched the tumor cells from death ligands sensitive to resistant using CRISPR/Cas9 and subsequently engineered them to release dual cell killing and immunomodulatory agents. These engineered therapeutic tumor cells (ThTC) eliminated established tumor and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling. This mechanism-based efficacy of ThTC translated into a marked survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompromised, immunocompetent and humanized mice. Arming naturally neoantigen-rich tumor cells with multidisciplinary therapeutics represents promising cell-based immunotherapy for solid tumors and establishes a roadmap towards clinical translation. Citation Format: Kok-Siong Chen, Natalia Claire Mendonca, Paulo Borges, Khalid Shah. Developing a self-targeted cancer immunotherapy using engineered whole tumor cell-based vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 698.
Abstract 3233: A novel triple humanized B-hPD-1/hPD-L1/hCCR8 mouse model to evaluate in vivo efficacy of combination therapies
Authors: Linlin Wang, Xiao Liu, James Jin, Yuxiang Yu
Journal: Cancer Research (2023)

Abstract Regulatory T cells (Tregs) play an immunosuppressive role in the tumor microenvironment (TME), such that altering or depleting Treg function has emerged as an important anti-tumor strategy. Targeting CCR8, which is highly expressed in tumor-infiltrating Tregs, has shown its potency in reducing tumor burden and increasing responsiveness to immune-checkpoint blockade therapy. Collectively, this suggests a need for preclinical models that support Treg-targeted therapies. To address this, Biocytogen developed a triple humanized (B-hPD-1/hPD-L1/hCCR8) mouse model to evaluate in vivo efficacy of combination therapies. In this model, the full coding sequence of murine Ccr8 was replaced by the full coding sequence of human CCR8, while murine Pd-1 and Pd-l1 IgV domains were replaced by their human counterpart gene sequences. Human PD-1 and PD-L1 protein expression was confirmed in B-hPD-1/hPD-L1/hCCR8 mice by flow cytometry, and human CCR8 protein expression was observed in MC38 tumors harvested from B-hPD-1/hPD-L1/hCCR8 mice. Finally, combination therapy using anti-human PD-1 and anti-human CCR8 antibodies were effective in controlling B-hPD-L1 MC38 tumor growth in B-hPD-1/hPD-L1/hCCR8 mice. Altogether, this line provides a powerful preclinical model for in vivo evaluation of therapeutic antibodies. Citation Format: Linlin Wang, Xiao Liu, James Jin, Yuxiang Yu. A novel triple humanized B-hPD-1/hPD-L1/hCCR8 mouse model to evaluate in vivo efficacy of combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3233.
Abstract 6725: Targeting urea cycle dysfunction to prevent and treat osteosarcoma
Authors: Rachel Offenbacher, Paul Ciero, David Loeb
Journal: Cancer Research (2023)

Abstract Introduction: Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents and young adults. Intensive multimodal treatment cures almost 75% of patients who present with localized disease; however, only 25% of patients who present with metastases become long term survivors, and those who suffer a metastatic relapse are almost never cured. Polyamine metabolism and signaling play important roles in multiple cancers but have not previously been studied in osteosarcoma. D, L-alpha-difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the initial, rate-limiting enzyme within the polyamine biosynthetic pathway, and has been studied in a number of different cancers as either a therapeutic or a chemopreventive agent. We investigated the role of polyamines in OS proliferation and metastasis and whether blocking the polyamine synthetic pathway with DFMO had therapeutic potential in the treatment of OS. Methods: We evaluated proliferation, apoptosis, clonogenic growth and the ability to grow under nonadherent conditions in vitro using established OS lines. To investigate the effect of DFMO on tumor growth in vivo, we implanted fragments of patient derived xenograft into the tibias of NOD/SCID/IL-2Rγ null mice. Upon confirmation of tumor growth, mice were randomized to either receive drinking water or drinking water supplemented with 2% DFMO. A third cohort of mice received water supplemented with 2% DFMO only after hindlimb amputation. Results: DFMO has a profound effect on the proliferation of OS cell lines in vitro. Utilizing caspase assays, we determined that DFMO does not induce apoptosis, but is cytostatic and inhibits proliferation. We found that DFMO prevents the clonogenic growth of 3 different OS cell lines in soft agar and prevents spheroid formation under non-adherent conditions. Interestingly, once established, spheroidss were not disrupted by the addition of DFMO. In vivo, administration of 2% DFMO after hindlimb amputation decreased local recurrence and limited metastasis (p=0.02). Conclusion: DFMO inhibits proliferation and clonogenic growth in vitro, and decreases distant metastasis in vivo. Since pediatric dosing and safety data are already established, our findings are readily translatable to clinical trials. Citation Format: Rachel Offenbacher, Paul Ciero, David Loeb. Targeting urea cycle dysfunction to prevent and treat osteosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6725.
Abstract 66: Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment
Authors: Dhanya K. Nambiar, Vignesh Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, Christina Kong, Rachel Hildebrand, Amanda Koong, Rie Eyben, Amato Giaccia, Lingyin Li, Edgar Engleman, Quynh Thu Le
Journal: Cancer Research (2023)

Abstract Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (Gal1) is a known modulator of tumor growth and progression in multiple cancer types including head and neck cancer (HNC). However, its contribution to the regulation of metastasis is poorly understood. Through this study we report a previously unknown role for Gal1 in modulating the STING pathway to regulate metastasis. The cGAS-STING pathway has paradoxical roles in cancer depending on the kinetics and strength of its induction, with chronic STING activation being linked to immune suppression and tumor progression while acute activation being associated with immune activation. However, little is known about the pathways that promote chronic STING activation. Using HNC and lung cancer models, we show that Gal-1 enhances STING protein stability, leading to sustained NF-κΒ activation and heightened chemokine-driven recruitment of myeloid derived suppressor cells (MDSCs). We show that Gal1-STING connection fosters the establishment of pre-metastatic niche through polymorphonuclear MDSCs (PMN-MDSCs), which modify the local lung microenvironment to support metastatic spread. Notably, RNA sequencing of MDSCs isolated from pre-metastatic lungs indicate the role of PMN-MDSCs in remodeling collagen and the extracellular matrix in the pre-metastatic compartment. Our findings reveal an unexpected role of STING activation in metastatic progression of HNC and lung cancer models and establish Gal1 as an endogenous positive regulator of STING. Citation Format: Dhanya K. Nambiar, Vignesh Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, Christina Kong, Rachel Hildebrand, Amanda Koong, Rie Eyben, Amato Giaccia, Lingyin Li, Edgar Engleman, Quynh Thu Le. Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 66.
Abstract PL04-05: LAG3: The third checkpoint inhibitor
Authors: Dario A. Vignali
Journal: Cancer Research (2023)

Abstract Immunotherapies targeting the PD1/PDL1 pathway have had a major impact on cancer treatment. However, only a proportion of patients respond, and an even smaller proportion exhibit a long-term, durable cure. Several mechanisms of resistance and potential combinatorial approaches will be discussed. Lack of response to inhibitory receptor (IR) blockade therapy and increased disease burden has been associated with circulating, peripheral CD8+ T cell exhaustion, which is defined by poor T cell function linked to increased IR expression (eg: PD1, LAG3, neuropilin-1 [NRP1]). LAG3 is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. However, persistent antigen exposure in the tumor microenvironment results in sustained PD1/LAG3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. This presentation will include a brief introduction LAG3, discussion of the signaling mechanism used by LAG3, and assessment of new insight in to the function of LAG3, alone and in combination with PD1, from mouse models of cancer and analysis of samples from patients treated with LAG3/PD1 therapeutics. Citation Format: Dario A. Vignali. LAG3: The third checkpoint inhibitor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr PL04-05.
Abstract 3606: HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis
Authors: Michael Emmons, Richard Bennett, Alberto Riva, Chao Zhang, Robert Macaulay, Daphne Dupéré-Richér, Bin Fang, John Koomen, Jiannong Li, Ann Chen, Edward Seto, Jonathan Licht, Keiran Smalley
Journal: Cancer Research (2023)

Abstract Melanomas are heterogeneous and adopt multiple transcriptional states that can confer an invasive phenotype and resistance to therapy. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity and tumor progression. Here we identify stress-induced HDAC8 activity as the driver of a neural crest stem cell (NCSC)-like transcriptional state that increased the formation of melanoma brain metastases (MBM). Exposure of melanocytes and melanoma cells to multiple different stresses led to HDAC8 activation, a switch to a NCSC gene expression signature and the adoption of an amoeboid, invasive phenotype. This cell state enhanced the survival of melanoma cells under shear stress conditions and increased the formation of metastases in the brain. Single cell RNA-seq analyses showed that HDAC8 expression was correlated with the NCSC cell state in clinical MBM specimens. ATAC-Seq and ChIP-Seq analysis showed HDAC8 to alter chromatin structure by increasing H3K27ac and accessibility at c-Jun binding sites without changing global histone acetylation. The increased accessibility of Jun binding sites was paralleled by decreased H3K27ac and accessibility at MITF binding sites and loss of melanoma-lineage gene expression. Mass spectrometry-based acetylomics demonstrated that HDAC8 deacetylated the histone acetyltransferase (HAT) EP300 leading to its enzymatic inactivation. This, in turn, led to an increased binding of EP300 to Jun-transcriptional sites and decreased binding to MITF-transcriptional sites. Increased expression of EP300 decreased invasion and increased the sensitivity of melanoma cells to multiple stresses while inhibition of EP300 function increased invasion and resistance to stress. We identified HDAC8 as a novel mediator of transcriptional co-factor inactivation and chromatin accessibility that increases MBM development. Citation Format: Michael Emmons, Richard Bennett, Alberto Riva, Chao Zhang, Robert Macaulay, Daphne Dupéré-Richér, Bin Fang, John Koomen, Jiannong Li, Ann Chen, Edward Seto, Jonathan Licht, Keiran Smalley. HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3606.
Abstract 4828: Therapeutic targeting of P2 × 4 receptor and mitochondrial membrane potential in renal cell carcinoma
Authors: Christopher Rupert, Roberto Pili, Filomena DeNigris
Journal: Cancer Research (2023)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common lethal subtype of kidney cancer. Large-scale metabolomics data have associated metabolic alterations with the pathogenesis and progression of renal cell carcinoma and have correlated mitochondrial activity with poor patient survival. Our group has recently reported that the lysosome purinergic receptor P2 × 4 (P2 × 4R) regulates neoangiogenesis. As ccRCC is characterized by increased angiogenesis we hypothesized that P2 × 4R may play a role in this disease. Interestingly, TCGA data suggest that P2 × 4R over-expression correlates with poor overall ccRCC patient survival. Our preliminary results also suggest that oxophosphorylation is the main source of tumor-derived ATP, which exerts a critical impact on tumor energy metabolism and mitochondrial activity in ccRCC. P2 × 4 receptor expression appears to contribute to the homeostasis of intracellular calcium and integrity of mitochondrial membrane potential in different ccRCC models. Seahorse experiments showed that P2 × 4R inhibition by 5BDBD, a potent and selective antagonist, caused a rapid dose-dependent reduction of mitochondrial activity. Moreover, prolonged mitochondrial failure induced by 5BDBD was associated with increased radical oxygen species, changes in mitochondrial permeability (i.e. opening of the transition pore complex, dissipation of membrane potential and calcium overload), and cell death via both necrosis and apoptosis. P2 × 4R inhibition by 5BDBD was associated with a significant anti-tumor effect both in vitro and in vivo by utilizing several ccRCC cell lines and patient-derived organoids. Interestingly, higher mitochondrial activity was associated with greater sensitivity to 5BDBD. Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2 × 4R inhibition may be a therapeutic strategy for a subset of renal carcinoma patients Citation Format: Christopher Rupert, Roberto Pili, Filomena DeNigris. Therapeutic targeting of P2 × 4 receptor and mitochondrial membrane potential in renal cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4828.
Abstract 1448: The YAP1/TEAD and NF-Kappa B transcription factors may cooperate to mediate prostate cancer progression
Authors: Bekir Cinar, Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Ava M. Boston, Michael S. Lewis, Carlos S. Moreno
Journal: Cancer Research (2023)

Abstract Metastatic castration-resistant prostate cancer is morbid and lethal. The transcriptional coregulator YAP1 (Yes-associated protein 1) is a nuclear effector of the Hippo pathway. The Hippo pathway regulates cell growth, motility, and carcinogenesis. Here, we investigated biochemical and functional interactions between YAP1 and the nuclear factor (NF) kappa B/RELA subunit in prostate cancer cell models. We demonstrated that endogenous YAP1 and RELA form protein complexes in the cell, as revealed by co-immunoprecipitation and western blotting. Compared with control, we found that combined treatment of cells with androgen and SDF1a (stromal cell-derived factor-1 alpha) or RANKL (receptor activator of NF-kappa Β ligand) enhanced the protein-protein interaction between YAP1 and RELA, as showed by proximity ligation assay. Our confocal microscopy experiment further showed that combined SDF1a and androgen treatment augmented the YAP1 and RELA colocalization relative to single-agent. Moreover, our promoter-reporter and RNAi experiments showed that genetic silencing YAP1 or TEAD protein, a key mediator of the YAP1 transcription, significantly reduced the NF-Kappa B promoter-reporter gene activity. Also, disruption of YAP1 activity by genetic and small molecule attenuated endogenous protein-protein interaction between TEAD and RELA. Furthermore, controlled expression of MST1/STK4, a potent inhibitor of YAP1, suppressed the NF-Kappa B-promoter reporter activity. Additionally, our unbiased bioinformatics analysis of the exiting ChIP-seq (chromatin immunoprecipitation-sequencing) data identified several genes likely co-regulated by the TEAD1-4 and NF-Kappa B transcription factors. Besides, our computational analysis of the TCGA and Stand Up To Cancer (SU2C) prostate cancer data sets indicated that expression of YAP/TEAD and NF-kappa B/RELA correlates in clinical cases. These findings suggest that cooperative androgen and cytokine signaling regulates Hippo/YAP and NF-Kappa B interaction and their functions. These may have critical roles in advanced prostate cancer downstream of the Hippo pathway. Citation Format: Bekir Cinar, Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Ava M. Boston, Michael S. Lewis, Carlos S. Moreno. The YAP1/TEAD and NF-Kappa B transcription factors may cooperate to mediate prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1448.